This research program will continue to investigate the mediators and modulation of pain. In the past, we focused on inhibitory modulation. During the current funding period, however, we also characterized a facilitatory component to the modulation of nociception. Experiments proposed for the next project period will continue to quantitatively study the facilitatory component of nociceptive modulation and, in addition, will examine the release and role(s) of local, spinal mediators in nociception. The Specific Aims are to: 1. quantitatively characterize the facilitatory modulation of (1) spinal nociceptive withdrawal reflexes evoked by noxious cutaneous thermal and mechanical stimuli and (2) spinal projection and spinothalamic lumbar dorsal horn neuron responses to both noxious and non-noxious cutaneous thermal and mechanical stimuli. These studies will include examination of the supraspinal circuitry/relays, spinal pathways and spinal neurotransmitters that mediate descending facilitation. 2. to examine the role(s) of excitatory amino acids, prostanoids and nitric oxide (NO) in local, spinal mediation of noxious thermal and mechanical transmission. 3. to examine the role(s) of prostanoids and NO as mediators of nociception in sensory neurons by studying their release from dorsal root ganglion cells maintained in culture. These Specific Aims are a logical extension of the current project and will continue a focused, systematic investigation into the mechanisms and modulation of nociception. Previous work on this project provides the necessary converging background information against which to meaningfully compare and interpret the results expected in the proposed studies. The proposed experiments will quantitatively examine (1) the facilitatory component of descending modulation and (2) local mediation and modulation of nociception.